The goal of this competing continuation grant is to improve the breast tumor diagnostic capabilities of optical spectroscopy and imaging based on diffusing near infrared light. Application of near-infrared optical methods for breast tumor imaging and specification is attractive. The techniques utilize non-ionizing radiation, are non-invasive, and are often technologically simple and fast. The method also has several unique measurable parameters with potential to enhance tumor sensitivity and specificity. Blood dynamics, blood volume, blood oxygen saturation, and water content are often substantially different in the rapidly growing tumor, and will alter tissue optical absorption coefficients. An increase in organelle population, e.g. mitochondria, accompanies the higher metabolic activity of the rapidly growing tumor, and leads to an increasing scattering coefficient for the tumor. Similarly the optical absorption, fluorescence, about and scattering of contrast agents that occupy vascular and extravascular space provide useful forms of sensitization. During the first two years of the original application, the applicants investigated the angular spectrum approach for diffuse optical tomography of the human breast in the parallel plate (compressed breast) geometry. They also built and tested a soft compression plate apparatus with tissue phantoms and in a few clinical scenarios. In carrying out this work the applicants reported having identified three targets wherein continued progress is critical to transfer this methodology from the developmental stage toward application. The first target area develops parallel computer based l image reconstruction algorithms for the diffusive wave inverse problem. This new power enables them to carry out 3 dimensional Finite Element and Finite Difference calculations on realistic timescales using realistic breast tissue samples and voxel sizes. The second target area adapts an existing frequency domain diffusive-wave compression plate apparatus for optical mammography to include a CCD in the detection plane (first at zero frequency and then modulated). The acquisition time for the CCD is so rapid that, by comparison to previous breast tomography with diffusive waves, they expect to generate >10,000 times more usable optical data for image reconstruction in a typical examination time of about 10 minutes. The combination of cw and modulated sources/detectors dramatically increases the amount of information available for image reconstruction, and thus takes full advantage of the parallel computing, codes developed in the theoretical part of the proposal. The third target of the program is clinical. They will perform pilot diffuse optical tomography on normal and high-risk patient populations with the assembled device and software.